Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements
The RAS-MAPK system plays an important role in regulating various cellular processes, including growth, differentiation, apoptosis, and transformation. Dysregulation of this system has been implicated in genetic diseases and cancers affecting diverse tissues. To better understand the regulation of t...
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eLife Sciences Publications Ltd
2025-03-01
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| Online Access: | https://elifesciences.org/articles/104432 |
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| author | Nobuhisa Umeki Yoshiyuki Kabashima Yasushi Sako |
| author_facet | Nobuhisa Umeki Yoshiyuki Kabashima Yasushi Sako |
| author_sort | Nobuhisa Umeki |
| collection | DOAJ |
| description | The RAS-MAPK system plays an important role in regulating various cellular processes, including growth, differentiation, apoptosis, and transformation. Dysregulation of this system has been implicated in genetic diseases and cancers affecting diverse tissues. To better understand the regulation of this system, we employed information flow analysis based on transfer entropy (TE) between the activation dynamics of two key elements in cells stimulated with EGF: SOS, a guanine nucleotide exchanger for the small GTPase RAS, and RAF, a RAS effector serine/threonine kinase. TE analysis allows for model-free assessment of the timing, direction, and strength of the information flow regulating the system response. We detected significant amounts of TE in both directions between SOS and RAF, indicating feedback regulation. Importantly, the amount of TE did not simply follow the input dose or the intensity of the causal reaction, demonstrating the uniqueness of TE. TE analysis proposed regulatory networks containing multiple tracks and feedback loops and revealed temporal switching in the reaction pathway primarily responsible for reaction control. This proposal was confirmed by the effects of an MEK inhibitor on TE. Furthermore, TE analysis identified the functional disorder of a SOS mutation associated with Noonan syndrome, a human genetic disease, of which the pathogenic mechanism has not been precisely known yet. TE assessment holds significant promise as a model-free analysis method of reaction networks in molecular pharmacology and pathology. |
| format | Article |
| id | doaj-art-3cfd05d33dbd4ee2ace807d74c5d4319 |
| institution | DOAJ |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-3cfd05d33dbd4ee2ace807d74c5d43192025-08-20T03:02:05ZengeLife Sciences Publications LtdeLife2050-084X2025-03-011410.7554/eLife.104432Evaluation of information flows in the RAS-MAPK system using transfer entropy measurementsNobuhisa Umeki0Yoshiyuki Kabashima1Yasushi Sako2https://orcid.org/0000-0002-5707-5455Cellular Informatics Laboratory, RIKEN, Cluster for Pioneering Research, Wako, JapanInstitute for Physics of Intelligence, The University of Tokyo, Bunkyo-ku, Japan; Trans-Scale Quantum Science Institute, The University of Tokyo, Bunkyo-ku, JapanCellular Informatics Laboratory, RIKEN, Cluster for Pioneering Research, Wako, JapanThe RAS-MAPK system plays an important role in regulating various cellular processes, including growth, differentiation, apoptosis, and transformation. Dysregulation of this system has been implicated in genetic diseases and cancers affecting diverse tissues. To better understand the regulation of this system, we employed information flow analysis based on transfer entropy (TE) between the activation dynamics of two key elements in cells stimulated with EGF: SOS, a guanine nucleotide exchanger for the small GTPase RAS, and RAF, a RAS effector serine/threonine kinase. TE analysis allows for model-free assessment of the timing, direction, and strength of the information flow regulating the system response. We detected significant amounts of TE in both directions between SOS and RAF, indicating feedback regulation. Importantly, the amount of TE did not simply follow the input dose or the intensity of the causal reaction, demonstrating the uniqueness of TE. TE analysis proposed regulatory networks containing multiple tracks and feedback loops and revealed temporal switching in the reaction pathway primarily responsible for reaction control. This proposal was confirmed by the effects of an MEK inhibitor on TE. Furthermore, TE analysis identified the functional disorder of a SOS mutation associated with Noonan syndrome, a human genetic disease, of which the pathogenic mechanism has not been precisely known yet. TE assessment holds significant promise as a model-free analysis method of reaction networks in molecular pharmacology and pathology.https://elifesciences.org/articles/104432RAS/MAPK systemsignal processingsingle-cell analysistransfer entropy |
| spellingShingle | Nobuhisa Umeki Yoshiyuki Kabashima Yasushi Sako Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements eLife RAS/MAPK system signal processing single-cell analysis transfer entropy |
| title | Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements |
| title_full | Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements |
| title_fullStr | Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements |
| title_full_unstemmed | Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements |
| title_short | Evaluation of information flows in the RAS-MAPK system using transfer entropy measurements |
| title_sort | evaluation of information flows in the ras mapk system using transfer entropy measurements |
| topic | RAS/MAPK system signal processing single-cell analysis transfer entropy |
| url | https://elifesciences.org/articles/104432 |
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